The present invention provides a method for protecting a variety of normal cells and tissues from injury produced by cytotoxic agents administered for the purpose of cancer therapy (chemotherapeutic agents). Specifically, it has been found that prostaglandins can protect normal tissues, such as hair and hair follicles and the hematopoietic system including protection of white blood cell (WBC) precursors in the bone marrow, from injury resulting from the administration of chemotherapeutic agents. Other tissues which can be protected include but are not limited to the following: skin; the gastrointestinal tract including stomach (gastric tissue), small intestine, colon and colo-rectal tissue; the esophagus, the mouth, including the oral mucosa; kidney, vagina, bladder, nasal passages, and eye. Prevention of tissue injury may be beneficial in reducing the morbidity of cancer chemotherapy and/or allowing for a higher and more curative dose regimen of chemotherapy to be delivered to cancer patients without damage or with minimized damage to the normal cells of such tissues.
The present invention relates to a method for protecting a variety of types of normal cells and tissues in the body from injury produced by chemical agents commonly used in the chemotherapy of human cancer. It has been found that the systemic administration or the topical application of misoprostol, [also known as (.+-.) (16RS)-15-deoxy-16-hydroxy-16-methyl prostaglandin E.sub.1, methyl ester and commercially available as Cytotec.RTM. from G. D. Searle & Co.] or the systemic administration of (.+-.)methyl 7-[3.alpha.-hydroxy-2.beta.-(4R-hydroxy-4-methyl-1E,5E,7E-nonatrienyl)-5-o xo-1.alpha.-cyclopentyl]-4Z-heptenoate, or 16,16-dimethyl prostaglandin E.sub.2 or PGE.sub.1 prior to the administration of cytotoxic chemotherapeutic agents serves to protect animals from death and/or protects different cell types in normal tissues from injury or damage caused by chemotherapeutic agents.
People diagnosed as having cancer are frequently treated with single or multiple cytotoxic chemotherapeutic agents (cytotoxic agents) to kill cancer cells at the primary tumor site or at distant sites to where cancer has metastasized. Chemotherapy treatment is given either in a single or in several large doses or, more commonly, it is given in small doses 1 to 4 times a day over variable times from weeks to months. There is a large number of cytotoxic agents used to treat cancer and the mechanisms of the cytotoxic effects of each agent is frequently not known or only partially known. Irrespective of the mechanism, useful chemotherapeutic agents are known to injure and kill cells of both tumors and normal tissues. The successful use of chemotherapeutic agents to treat cancer depends upon the differential killing effect of the agent on cancer cells compared to effects on critical normal tissues. The effects of chemotherapeutic agents on normal tissues are referred to as side-effects of cancer treatment. The immediate side effects (minutes to a few hours) of chemotherapy may include dizziness, nausea, vomiting, and diarrhea. These side effects are uncomfortable but, in themselves, are not life-threatening. Cell killing or damage within normal tissues that occurs from days to weeks during a course of chemotherapy may result in uncomfortable and/or life threatening side effects. Among these effects are hair loss, hearing loss, sterility, damage to the mucosal epithelium of the gastrointestinal tract, damage to the oral mucosa, esophagus, small and large intestines, kidney damage, skin damage, cardiac damage, killing and suppression of the white blood cells which can lead to infection, and killing of hematopoietic blood forming cells. Many of these side effects are related to tissues and organ systems that have a high number of dividing cells (proliferative cells). Some of these side effects are non-life threatening; however, a reduction or prevention of these effects could have a beneficial effect on cancer patients or make it possible to administer a higher dose of the chemotherapeutic agent while minimizing damage or death of cells in normal tissue.
Hair loss (alopecia) caused by chemotherapeutic agents is an example of a non-life-threatening side effect which can be prevented or minimized. Alopecia is typically viewed by both male and female patients as a sign of rapid progress of their disease and not as a side effect of the chemotherapy treatment. Alopecia frequently produces anxiety and a loss of self esteem in cancer patients. A reduction or prevention of non-life threatening side effects of chemotherapy such as alopecia could increase a cancer patient's quality of life and outlook during treatment.
Other side effects of chemotherapy treatment are life threatening and thus limit the doses of chemotherapeutic agents that can safely be delivered to a cancer patient undergoing treatment. A reduction or prevention of dose-limiting, life-threatening side effects of chemotherapy could reduce the risk of injury or death of normal cells in the patient and possibly allow the administration of a larger dose of chemotherapeutic agents, thereby increasing the longevity and the number of survivors following chemotherapy.
Prevention or protection from the side effects of chemotherapy would be a great benefit to cancer patients. Previous efforts to reduce these side effects have been many, varied and largely unsuccessful. For non-life-threatening side effects, little effort has been expended. Attempts to prevent hair loss, for example, have included use of a cold cap or tourniquets to reduce drug concentrations in the scalp. Patient compliance is poor and these methods are infrequently used. More recently, a compound called ImuVert (made by Cell Technology, Inc.) has been reported to reduce hair loss in rats given anti-cancer agents, but the flu-like side effects make it impractical (See Hussein, A. M.; Jimenez, J. J.; McCall, C. A.; Yunis, A. A., Protection from Chemotherapy Induced Alopecia in a Rat Model. Science 249:1564-1566; 1990).
For life-threatening side effects, efforts have concentrated on altering the dose and schedules of the chemotherapeutic agent to reduce the side effects. Other options are becoming available, such as the use of colony stimulating factor (CSF), granulocyte-macrophage-CSF (GM-CSF) or epidermal growth factor (EGF) to increase the number of normal cells in various tissues before the start of chemotherapy (See Jimenez, J. J.; Yunis, A. A. Protection from 1-.delta.-D-Arabinofuranosylctosine-Induced Alopecia by Epidermal Growth Factor and Fibroblast Growth Factor in the Rat Model. Cancer Research 52:413-415; 1992). The mechanisms of protection by these factors, while not fully understood, are most likely associated with an increase in the number of normal critical target cells before treatment with cytotoxic agents.
There are few compounds which provide direct protection from injury caused by chemotherapy. One agent that has been reported to protect the kidney from injury caused by bolus infusions of cisplatin is S-2-(3-aminopropylamino) ethylphosphorothioxic acid (WR2721). (See Glover, D.; Fox, K. R.; Weiler, C.; Kligerman, M. M.; Turrisi, A.; Glick, J. H. Clinical Trials of WR-2721 Prior to Alkylating Agent Chemotherapy and Radiotherapy. Pharmacology and Therapeutics 39:3; 1988). This compound appears to have limited usefulness and is effective only for large single doses of the chemotherapy agent, since WR-2721 itself given in large protective doses causes hypotension, nausea, and vomiting in humans. These toxicities increase with daily use and, as a result, have been found ineffective given over the days to weeks of typical chemotherapy regimens.
It would be desirable to provide effective protection from chemotherapy side effects. It would be desirable to provide such protection by a simple procedure which would assure compliance and not interfere with the beneficial therapeutic properties of the chemotherapy agents.
Prostaglandins are known for their protective properties associated with the gastric and intestinal mucosa. They are recognized for their protective properties with respect to ethanol-induced injury to the G.I. tract, NSAID induced injury to the G.I. tract and to radiation-induced injury. The mechanism associated with ethanol injury appears to be related to mucous secretion and/or bicarbonate secretion. There is no apparent causal link between prostaglandins and WR-2721 which compound has been shown to protect from cisplatin injury.
U.S. Pat. No. 4,081,553 (to Robert), provides a method for the treatment of intestinal inflammatory disease caused by radiation exposure, as well as a method of treatment for Crohn's disease, inflammatory bowel disease, infectious enteritis, sprue and intestinally manifested allergic responses to foodstuffs by administering a cytoprotective prostaglandin to a patient suffering from one of these diseases. Such cytoprotective prostaglandins modify inflammatory infiltration into gastric or intestinal tissue and are administered after injury to the tissue.
U.S. Pat. No. 4,097,603 (to Robert) discloses a method of protecting gastric tissue from gastric inflammatory disease and ulcerative (erosive) diseases by administration of prostaglandins, including prophylactic administration 30 minutes prior to administration of an inflammation causing agent. The type of injuries to gastric tissue discussed by Robert are injuries resulting from inflammation of such tissue. Robert mentions that suitable subjects for treatment by the disclosed methodology include patients exposed to noxious agents such as household cleaners and chemotherapeutic agents.
The mechanisms of protection by prostaglandins of gastric and intestinal tissue are associated with increased mucous secretion or increased bicarbonate secretion. (See T. A. Miller, Am. J. Physiol., 245:G601-G623, 1983). Such increased secretions are unique to the physiology of gastric and intestinal tissue and such mechanisms would not be possible in non-mucous and/or non-bicarbonate secreting tissue.
The present invention provides cell protection for several non-mucous producing and non-bicarbonate producing tissues, such as hair follicles, bone marrow and skin, from cell injury caused by chemotherapeutic agents. Additionally, the present invention provides for protection of normal tissue from actual cell death which is distinct from the protection of stomach and intestinal tissue from inflammatory diseases. Thus, it is postulated that the mechanism of action of the E-type prostaglandins of the present invention is unique and distinct from the proposed mechanism of action of PG induced protection of stomach tissue or intestinal tissue from inflammation.